Dendritic cells are bone marrow derived cells, sparsely distributed in lymphoid organs, blood and peripheral tissues, that are critical in the initiation and maintenance of an immune response. DC share common properties such as antigen (Ag) processing and the ability to activate naïve T cells. However DC are heterogeneous, with at least seven distinct subtypes detected in the mouse (Shortman and Liu, 2002).
DC can be broadly classified into conventional DC (cDC) and plasmacytoid pre-DC (pDC). The pDC are able to secrete high levels of IFNα and only develop into DC upon activation (O'Keeffe et al., 2002; Hochrein et al., 2001). The cDC may be divided into the classical “migratory” or interstitial DC (such as Langerhans' cells), which migrate to the lymph nodes (LN) from peripheral tissues via the lymph and the “lymphoid tissue resident” DC (found in spleen, thymus and LN), which do not migrate in this way but which arise from blood-borne precursors.
The lymphoid tissue resident DC of mice may in turn be divided into the CD4−8− (DN), the CD4+8− (CD4+) and the CD4−8+ (CD8+) cDC subsets, where the CD4 and DN are collectively referred to as the CD8− DC. In addition, there are inflammatory DC which develop as a consequence of infection or inflammation (Shortman and Naik, 2007). These DC subtypes share many functions, especially the uptake, processing and presentation of antigen (Ag) to activate naïve T cells.
Importantly, DC also exhibit subset-specific roles. Different DC subtypes express different patterns of Toll-like receptors (TLR) and consequently vary in their capacity to respond to different infections (Proietto et al., 2004; Takdea et al., 2003). Whilst chemokine production is carried out primarily by CD8− DC, the CD8+ DC are the major producers of IL-12, which directs a Th1 T cell response. The capacity to cross-present exogenous Ags via MHC class 1 molecules, is an activity performed very efficiently by the CD8+ DC subset (Pooley et al., 2001; den Haan et al., 2000), which allows these DC to be major presenters of viral Ag to CD8+ T cells (Belz et al., 2004; Smith et al., 2003). By contrast, CD8− DC appear better equipped for initiating MHC class II restricted responses (Dudziak et al., 2007; Schnorrer et al., 2006).
Molecules on the surface of DC are important in the recognition, communication and activation functions of DC. The molecules that differ between DC subtypes are of interest, since they may underpin the functional differences observed between these subtypes. Furthermore, surface molecules differing between the DC subtypes are of special interest, since they may serve as beacons for selective delivery to the DC of Ag or therapeutic agents in order to manipulate immune responses.
Antibodies (Ab) against DC cell surface molecules have been used to deliver Ag to DC and induce tolerance (Bonifaz et al., 2002; Finkelman et al., 1996). Immunity to the targeted Ag has also been induced, although in most studies only when the antibody-antigen complex is co-administered with a DC maturation agent or adjuvant (Bonifaz et al., 2002; Carter et al., 2006). Importantly, the efficiency of targeting Ag using cell surface molecules and raising immunity will depend on several factors: (i) the subset of DCs targeted; (ii) dose-dependent effects relating to the expression level of the targeted molecules; (iii) the expression of the targeted molecule on cell types other than DC, which may limit the effectiveness of targeting or potentially introduce contributions by these non-DC; (iv) the function of the targeted molecule, which may affect Ag processing or deliver signals that induce or impair DC maturation; (v) the TLR profile of the targeted DC subset, particularly when TLR ligands are co-administered. All of the above factors will impact the ability to raise immune responses in a clinical setting. Of necessity, these details must first be established with experimental animals such as mice, before translation to humans. Thus, what is needed for targeting Ag to DC and efficient vaccination is a DC surface molecule that is conserved between mouse and man, in terms of molecular and functional characteristics and restricted expression pattern.
It appears that humans contain equivalents of the murine DC subsets. The division into cDC and pDC is well established as is the presence of Langerhans' cells.
The close similarity between mouse and human DC when extracted from the same tissue source (thymus) (O'Keeffe et al., 2003; Vandenabeele et al., 2001) suggests a close similarity. However, the human equivalents of most of the murine “lymphoid organ resident” DC subsets remain unknown, due to the lack of conserved surface markers between species (i.e. the CD8 marker is not expressed on human DC) and the difficulty in obtaining samples of human lymphoid organs for analysis. What is needed to facilitate the translation of mouse biology into human clinical applications is the identification of DC subset-specific marker molecules conserved between mice, humans, and other species. Such surface molecules might allow the tailoring of immune responses by harnessing the specific immune functions of distinct DC subtypes.
There is a need for the identification of dendritic cell markers that can be used to target therapies, such as vaccines, to dendritic cells.